Associations of a family history of lupus with the risks of lupus and major psychiatric disorders in first-degree relatives Free

Summary

Background

Genetic factors link psychiatric disorders, particularly major depressive disorder (MDD), bipolar disorder, and obsessive-compulsive disorder (OCD), with systemic lupus erythematosus (SLE). Additionally, maternal SLE is a risk factor for long-term developmental problems, particularly learning disabilities, attention disorders, autism spectrum disorder (ASD) and speech disorders, in children.

Aim

We aimed to determine whether first-degree relatives (FDRs) of patients with SLE have increased risks of SLE and major psychiatric disorders.

Design and methods

Using the Taiwan National Health Insurance Research Database, we recruited 40 462 FDRs of patients with SLE as well as 161 848 matched controls. The risks of major psychiatric disorders, including schizophrenia, bipolar disorder, OCD, MDD, ASD and attention-deficit/hyperactivity disorder (ADHD), were assessed.

Results

The FDRs of patients with SLE had higher risks of SLE (reported as the adjusted relative risk and 95% confidence interval: 14.54; 12.19–17.34), MDD (1.23; 1.12–1.34), ADHD (1.60; 1.55–1.65), OCD (1.41; 1.14–1.74) and bipolar disorder (1.18; 1.01–1.38) compared with controls. Specifically, male FDRs of patients with SLE had higher risks of SLE and bipolar disorder, whereas female FDRs of patients with SLE had higher risks of MDD and OCD. Differences in the familial relationship (i.e. parents, children, siblings and twins) were consistently associated with higher risks of these disorders compared with controls.

Conclusions

The FDRs of patients with SLE had higher risks of SLE, MDD, ADHD, OCD and bipolar disorder than the controls.

Introduction

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that involves autoantibody production and tissue injury in multiple organ systems, including the central nervous system.¹ A strong genetic predisposition to SLE has been reported. For example, familial aggregation studies have demonstrated that siblings of patients with SLE have a 29-fold higher risk of SLE than the general population,² and monozygotic twins have a 10-fold higher risk of SLE than dizygotic twins.^3,4 Numerous genome-wide association studies have identified more than 40 risk loci linked to SLE susceptibility.^5,6

In addition, genetic factors link SLE with the risk of psychiatric symptoms,⁷ which occur in ∼5–70% of patients with SLE. Previous studies have reported that the prevalence of major depressive disorder (MDD) among patients with SLE was 11–39%, and the risk of MDD is 4-fold higher in patients with SLE than in the general population.^8,9 Another study reported that patients with SLE have a 6-fold higher risk of bipolar disorder¹⁰ and a 10- to 15-fold higher risk of obsessive-compulsive disorder (OCD)¹¹ compared with the general population. Moreover, a population-based study found that the proportion of individuals with schizophrenia in patients with SLE was higher than that in the general population (1.38% vs. 0.83%, P < 0.001).¹²

The strong influence of genetic factors on SLE risk and their association with psychiatric symptoms suggest that first-degree relatives (FDRs) of patients with SLE may have a higher likelihood of being diagnosed with SLE and psychiatric disorders than the general population. A previous systematic review indicated that maternal SLE is a risk factor for long-term developmental problems in children, including learning disabilities (especially dyslexia in male progeny), attention disorders, autism spectrum disorder (ASD) and speech disorders.¹³ To date, no studies have investigated the association between SLE and psychiatric disorders among the unaffected FDRs of patients with SLE. Thus, the aim of the present population-based study was to examine the risks of lupus and major psychiatric disorders in the FDRs of patients with SLE.

Materials and methods

Data source

Taiwan’s National Health Insurance was established in 1995, covering medical care for ∼99.6% of all Taiwanese residents by the end of 2010. The National Health Insurance Research Database (NHIRD) containing data on these insured patients is available upon formal request for scientific and study purposes.^14–16 The NHIRD provides comprehensive information on insured subjects, including demographic data and detailed clinical information (outpatient and inpatient care, dates of clinical visits, disease diagnoses, examinations, operations, prescriptions and procedures). Following the method of Chen et al.¹⁷ and Cheng et al.,¹⁸ family relationships recorded in the NHIRD were used to reconstruct genealogies. Only blood relatives or spouses qualified as dependents of the insured patients. A sibling relationship was confirmed if the patients shared the same father or mother. These siblings were identified as twins if they shared a birthdate; however, twin zygosity could not be determined from the NHIRD. Thus, each subject could have several different familial relationships identified through the database. The diagnostic codes used in the present study were based on the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). The NHIRD has been used extensively in many epidemiologic studies.^17–20 Our study used the unique identification number of patients to link all of the health care records of each beneficiary. This study was approved by the relevant Institutional Review Board.

Inclusion criteria and disease classification

In Taiwan, patients with suspected SLE (ICD-9-CM codes: 710 and 695.4) are referred to rheumatologists for diagnosis and treatment. After the diagnosis is confirmed, patients are permitted to waive medical copayments; therefore, diagnostic information is sent to the insurance administration for review by commissioned expert panels to confirm the diagnosis before approval waivers can be issued. The panel reviews the diagnosis in compliance with up-to-date classification criteria. The Registry for Patients with Catastrophic Illness contains information on these patients along with their unique personal identification codes, diagnosis, demographic characteristics, application date, diagnosing physician, hospital and other administrative data. We used this registry to identify patients with SLE.

We included all individuals with SLE diagnosed between March 1995 and December 2010. Then, we identified the FDRs of patients with SLE, including parents, children, siblings and twins. The enrolled controls were matched for age, sex and familial relationships at a 1:4 ratio. For example, a 51-year-old father of a daughter with SLE would be matched with four 51-year-old fathers of daughters without SLE.

We focused on six major psychiatric disorders, namely, MDD (ICD-9-CM codes: 296.2 and 296.3), bipolar disorder (ICD-9-CM code: 296 except for 296.2, 296.3, 296.9 and 296.82), schizophrenia (ICD-9-CM code: 295), ASD (ICD-9-CM code: 299), attention-deficit/hyperactivity disorder (ADHD; ICD-9-CM code: 314) and OCD (ICD-9-CM code: 300.3). These major psychiatric disorders were diagnosed by at least two board-certified psychiatrists according to their clinical assessment and comprehensive diagnostic interviews.

Assessment of covariates

Demographic characteristics, including age, sex, place of residence and income in 2010, were collected and adjusted for when calculating the relative risks. The place of residence was classified into five categories according to the level of urbanization. Monthly income was divided into three levels: ≤15 840 New Taiwanese dollars (NTD) [equivalent to 528 US dollars (USD)], 15 841–25 000 NTD (528–833 USD), or ≥25 000 NTD (≥833 USD). A monthly income of 528 USD (15 840 NTD) was the government-designated cut-off for the minimum income of full-time employment in Taiwan during the research period.

Statistical analysis

We used independent-sample t tests for continuous variables and Pearson’s χ² tests for categorical variables to assess differences between the FDRs of patients with SLE and the matched controls. The adjusted relative risks (ARRs) and 95% confidence intervals (CIs) were calculated to determine the risks of the six major psychiatric disorders for each specific FDR between cases and controls. All statistical analyses were performed using SPSS version 21.0 for Windows (IBM, Armonk, NY, USA) and SAS version 9.2 (SAS Institute, Cary, NC, USA). The PROC GENMOD method in SAS was used to estimate the ARRs in our study. All tests were two-tailed, and P < 0.05 was considered statistically significant.

Results

We included 40 462 FDRs of patients with SLE and 161 848 age-, sex-, and relationship-matched controls (Table 1). The mean age of FDRs of patients with SLE was 34.2 ± 18.3 years, and the male proportion was 50.2%. The distribution of residential location differed between the FDRs of patients with SLE and the matched controls (P < 0.001).

Risk of SLE in FDRs of patients with SLE

Among the FDRs of patients with SLE, 566 had SLE, a prevalence of 1.40% (Table 2). FDRs of patients with SLE had an increased risk of SLE compared with the controls (reported as ARR with 95% CI, 14.54; 12.19–17.34). In addition, male FDRs (25.30; 13.72–46.65) had a higher ARR of SLE than female FDRs (13.66; 11.36–16.44). Stratifying by familial relationship showed that the risk of SLE was highest for twins (95.77; 15.01–611.08), followed by siblings (22.37; 16.71–29.94), parents (10.36; 7.48–14.33) and children (10.03; 7.29–13.82). Stratifying by familial relationship and sex showed that brothers of patients with SLE had an ARR of 70.35 (16.82–294.25) compared with controls.

Risk of MDD in FDRs of patients with SLE

Among the FDRs of patients with SLE, 643 had MDD, a prevalence of 1.59% (Table 3). FDRs of patients with SLE had an increased risk of MDD compared with controls (1.23; 1.12–1.34). This risk was observed only in female FDRs (1.24; 1.13–1.37) but not male FDRs of patients with SLE (1.11; 0.84–1.46). Stratifying by familial relationship showed that the risk of MDD was highest for parents (1.37; 1.16–1.62), followed by siblings (1.22; 1.04–1.43) and children (1.16; 1.01–1.34). Stratifying by familial relationship and sex showed that the risk of MDD was 1.97 (1.09–3.57) in daughters of a father with SLE compared with controls.

Risk of ADHD in FDRs of patients with SLE

Among the FDRs of patients with SLE, 326 had ADHD, a prevalence of 0.81% (Table 4). FDRs of patients with SLE had an increased risk of ADHD compared with controls (1.60; 1.55–1.65). This risk was observed in both female FDRs (1.60; 1.55–1.65) and male FDRs of patients with SLE (1.61; 1.47–1.78). Stratifying by familial relationship showed that the risk of ADHD was highest for children (1.97; 1.23–2.57), followed by siblings (1.62; 1.51–1.73) and parents (1.59; 1.54–1.65).

Risk of OCD in FDRs of patients with SLE

Among the FDRs of patients with SLE, 117 had OCD, a prevalence of 0.29% (Table 5). FDRs of patients with SLE had an increased risk of OCD compared with controls (1.41; 1.14–1.74). Similar to MDD, this risk was observed in female FDRs (1.46; 1.17–1.82) but not in male FDRs of patients with SLE (1.00; 0.48–2.07). Stratifying by familial relationship, sex of FDRs and sex of patients showed that brothers of male patients with SLE had the highest risk of OCD (3.35; 1.02–11.05).

Risk of bipolar disorder in FDRs of patients with SLE

Among the FDRs of patients with SLE, 208 had bipolar disorder, a prevalence of 0.51% (Supplementary Table S1). FDRs of patients with SLE had an increased risk of bipolar disorder compared with controls (1.18; 1.01–1.38). In contrast to MDD, this risk was observed in male FDRs (1.66; 1.08–2.56) but not in female FDRs of patients with SLE (1.12; 0.95–1.33). Stratifying by relationship, sex of FDRs and sex of patients showed that females who had fathers with SLE had the highest risk of bipolar disorder (3.00; 1.23–7.32).

Risk of schizophrenia and ASD in FDRs of patients with SLE

Among the FDRs of patients with SLE, 219 had schizophrenia (Supplementary Table S2), and 59 had ASD (Supplementary Table S3), prevalence rates of 0.54% and 0.15%, respectively. A family history of SLE was not associated with an increased risk of schizophrenia and ASD among the FDRs.

Discussion

We found that the FDRs of patients with SLE had a 14.5-fold higher risk of SLE, a 1.6-fold higher risk of ADHD, a 1.4-fold higher risk of OCD and 1.2-fold higher risks of MDD and bipolar disorder compared with controls. The risks of major psychiatric disorders (except for ADHD) may correlate with sex of the FDRs and sex of the patients with SLE. For example, male FDRs of patients with SLE had higher risks of SLE and bipolar disorder, whereas female FDRs of patients with SLE had higher risks of MDD and OCD. The risk of SLE differed according to familial relationship, suggesting that genetic relatedness influences the magnitude of this risk. In brief, our findings suggest that a family history of SLE is a risk factor not only for SLE but also for ADHD, OCD, MDD and bipolar disorder among FDRs.

Previous studies have reported familial aggregation in SLE,^2,21 and our study found not only familial aggregation of SLE but also comorbidities with major psychiatric disorders in the FDRs of patients with SLE. We showed that the FDRs of patients with SLE had a 14.5-fold higher risk of SLE compared with controls and that kinship (i.e. genetic relatedness) is associated with the risk of SLE. In addition, our study supports the findings of previous epidemiological studies reporting an association between SLE and psychiatric disorders; it also extends these findings to other mental disorders, including MDD, ADHD, bipolar disorder and OCD. Our findings suggest that family members of patients with SLE are at risk for ADHD, OCD, MDD and bipolar disorder and are more likely to exhibit a neuropsychiatric endophenotype. Previous reports have shown that the anti-ribosomal protein P antibody is associated with psychiatric symptoms.²² Additionally, antibodies against the subunits of the N-methyl-D-aspartate receptor (anti-DNA/NR2 antibodies) are associated with anxiety disorders, mood disorders and psychosis.²³ Our findings suggest that the pathogenesis of SLE and these psychiatric disorders overlap. Disease activity in SLE may also contribute to psychiatric symptomatology through shared pathophysiological mechanisms, including antineuronal and antiphospholipid antibodies,²⁴ proinflammatory cytokines²⁵ and calcifications in the basal ganglia, a brain region implicated in OCD.²⁶ Furthermore, the effect of psychological stressors on caregivers of patients with progressive SLE as well as wider family networks is well recognized.²⁷ A higher incidence of psychiatric disorders in relatives of patients with SLE may result from disease-induced stress.

The major strengths of this study include its large population-based design, the reliable diagnostic criteria of the ICD, and our ability to identify more than 40 000 FDRs through the NHIRD. Previous reports have often been based on less robust sampling strategies and case ascertainment, such as hospital records, self-reported diagnoses and disease registries, therefore limiting their generalizability. However, this study also has several limitations. First, the classification of cases was based on the diagnosis code recorded in the Registry for Patients with Catastrophic Illness. We could not obtain detailed information on clinical findings, laboratory test results and examinations to confirm the diagnosis according to the formal classification criteria for SLE. Nevertheless, issuance of a catastrophic illness certificate in Taiwan requires strong medical evidence for an SLE diagnosis that is considered by an expert panel, and applications for these certificates are submitted almost exclusively by rheumatologists. Therefore, our case definitions were stringent. Second, this study was restricted to Taiwan; different findings may be obtained in other populations and regions. Therefore, additional studies in other countries are required to determine the generalizability of our findings. Third, the cluster effect (i.e. correlations between family members) may have affected our estimates of the RRs and 95% CIs. Fourth, some of the psychiatric disorders, especially mood disorders, might be underreported because many individuals with these disorders do not seek primary health care.

Conclusion

To our knowledge, this is the first nationwide study to examine the association of a family history of SLE with the risks of SLE and major psychiatric disorders in the FDRs of patients with SLE. We found that a family history of SLE was the strongest risk factor for the development of SLE, ADHD, OCD, MDD or bipolar disorder among FDRs. Importantly, the familial relationship, sex of FDRs and sex of patients with SLE may influence these risks. Our findings may inform further studies on the familial and genetic risks of SLE and its psychiatric comorbidities. Medical practitioners should closely monitor the mental health of FDRs of patients with SLE and highlight the risks for family members to promote early diagnoses and interventions.

Supplementary material

Supplementary material is available at QJMED online.

Funding

The study was supported by grants from Tri-Service General Hospital (TSGH-E-111229), Taipei Veterans General Hospital (V106B-020, V107B-010, V107C-181 and V108B-012), Yen Tjing Ling Medical Foundation (CI-109-21 and CI-109-22) and the Ministry of Science and Technology, Taiwan (107-2314-B-075-063-MY3 and 108-2314-B-075-037).

Conflict of interest: None declared.

References

Author notes